Body mass index modifies the relationship between gamma-H2AX, a DNA damage biomarker, and pathological complete response in triple-negative breast cancer

作者：Barba Maddalena; Vici Patrizia; Pizzuti Laura; Di Lauro Luigi; Sergi Domenico; Di Benedetto Anna; Ercolani Cristiana; Sperati Francesca; Terrenato Irene; Botti Claudio; Mentuccia Lucia; Iezzi Laura; Gamucci Teresa; Natoli Clara; Vitale Ilio; Mottolese Marcella; De Maria Ruggero; Maugeri Sacca Marcello

来源：BMC Cancer, 2017, 17(1): 101.

DOI：10.1186/s12885-016-3045-z

• Body mass index
• gamma-H2AX
• Chk1
• Double-strand breaks
• Pathological complete response
• Triple-negative breast cancer

Background: Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). Overweight and obesity are linked to a variety of pathways regulating tumor-promoting functions, including the DNA damage response (DDR). The DDR physiologically safeguards genome integrity but, in a neoplastic background, it is aberrantly engaged and protects cancer cells from chemotherapy. We herein verified the role of BMI on a previously assessed association between DDR biomarkers and pathological complete response (pCR) in TNBC patients treated with neoadjuvant chemotherapy (NACT).
Methods: In this retrospective analysis 54 TNBC patients treated with NACT were included. The relationship between DDR biomarkers, namely phosphorylated H2A Histone Family Member X (gamma-H2AX) and phosphorylated checkpoint kinase 1 (pChk1), and pCR was reconsidered in light of BMI data. The Pearson's Chi-squared test of independence (2-tailed) and the Fisher Exact test were employed to assess the relationship between clinical-molecular variables and pCR. Uni- and multivariate logistic regression models were used to identify variables impacting pCR. Internal validation was carried out.
Results: We observed a significant association between elevated levels of the two DDR biomarkers and pCR in patients with BMI < 25 (p = 0.009 and p = 0.022 for gamma-H2AX and pChk1, respectively), but not in their heavier counterpart. Results regarding gamma-H2AX were confirmed in uni- and multivariate models and, again, for leaner patients only (gamma-H2AX(high) vs gamma-H2AX(low): OR 10.83, 95% CI: 1.79-65.55, p = 0.009). The consistency of this finding was confirmed upon internal validation.
Conclusions: The predictive significance of gamma-H2AX varies according to BMI status. Indeed, elevated levels of gamma-H2AX seemed associated with lower pCR rate only in leaner patients, whereas differences in pCR rate according to gamma-H2AX levels were not appreciable in heavier patients. Larger investigations are warranted concerning the potential role of BMI as effect modifier of the relationship between DDR-related biomarkers and clinical outcomes in TNBC.

• 出版日期2017-2-6